WO2009156459A1

WO2009156459A1 - Organic compounds

Info

Publication number: WO2009156459A1
Application number: PCT/EP2009/057933
Authority: WO
Inventors: Bernhard Riss; Christian ZÜRCHER
Original assignee: Novartis Ag
Priority date: 2008-06-26
Filing date: 2009-06-24
Publication date: 2009-12-30
Also published as: UY31936A; TW201006809A; AR072295A1

Abstract

The present invention provides an improved process for the synthesis of 5,6-dimethyl-9-oxo-9H-xanthen 4-yl-acetic acid (DMXAA). The process yields pure and colorless product, and is suitable for large scale production.

Description

ORGANIC COMPOUNDS

Background of the Invention

Field of the Invention

The present invention provides highly efficient methods for the preparation of 5,6-dimethyl-9-oxo-9H-xanthen-4-yl-acetic acid (DMXAA).

Description of Related Art

5,6-Dimethyl-9-oxo-9H-xanthen-4-yl-acetic acid exhibits a wide array of biological activities. One approach to the synthesis of 5,6-dimethyl-9-oxo-9H-xanthen-4-yl-acetic acid is described in Rewcastle et al., J. Med. Chem., Vol. 34, p. 217 (1991) in a 6-step synthesis with an overall yield of around 12%. The development of an efficient method for the preparation of 5,6-dimethyl-9-oxo-9H-xanthen-4-yl-acetic acid still constitutes an important challenge.

Summary of the Invention

The present invention provides methods for the efficient preparation of 5,6-dimethyl~9- oxo-9H-xanthen-4-yl-acetic acid, which has the following formula (I):

or a salt of the compound.

The process for the synthesis of 5,6-dimethyl-9-oxo-9H-xanthen 4-yl-acetic acid yields pure and colorless product, and is suitable for large scale production. Furthermore, the process avoids isolating 5,6-dϊmethyl-9-oxo-9H-xanthen 4-yl-acetic acid from aqueous sulfuric acid, which has a long filtration time and cumbersome wash of residual sulfuric acid. The process shows several improvements in regards to safety and ecology. Crude 2-[2- (carboxylmethyl)phenoxy]-3,4-dimethylbenzoic acid, known as compound 4 can be purified using two alternative steps to produce the final product, 5,6-dimethyl-9-oxo-9H-xanthen 4-yl- acetic acid. Crude 2-[2-{carboxyImethyI)phenoxy]-3,4-dimethylbenzoic acid can be purified by re-crystallization or Crude 2-[2-(carboxylmethyl)phenoxy]-3,4-dimethylbenzoic add can be cyciized to produce 5,6-dimethyl-9-oxo-9H-xanthen 4-yl-acetic acid.

The invention is specific for the synthesis of 5,6-dimethyl-9-oxo-9H-xanthen 4-yl-acetic acid. However, the purification step may be useful for other sparingly soluble compounds which can be dissolved in water as their water soluble salt.

Detailed Description of the Invention

As described above, the present invention provides a process for the manufacture of 5,6-dimethyl-9-oxo-9H-xanthen 4-yl-acetic acid.

A method is illustrated in the following Scheme 1 :

Scheme 1

(2-Hydrøxy-phβnyl)-aeetlc acid 2-(2-Carf>oxytnβthy!-phenøxy)-3,4~ (5,6-Dlmβthyl-9-oxo-9H-xanthβn-4- dlmethyl-benzota add yl)-acβtie βcM a: NaNO₂ZH₂SO₄, 1₂ZKlZH₂O AcOEt, b; NaOMeZMeOH, AcOEt: c: KOtBuZDMF, CuCl; d; NaOH₁ H₂O, AcOEt, AcOH; e: H₂SO₄ (or MeSO₃H, AcOH, Ac₂O); f: NaOH, THF, AcOH, H₂O.

The process described in Scheme 1 avoids the need to isolate 5,6-dimethyl-9-oxo-9H- xanthen 4-yt-aeetic add.

The synthesis of compound 2 in scheme 1 above, known as 2-iodo-3,4- dimethoxybenzoic acid sodium salt, is produced in a high purity and high yield by minimizing the byproduct, dimethyl salicylic acid. The by-product is removed efficiently by the crystallization of the sodium salt in ethyl acetate. Furthermore, addition of heptanes helps to maintain the iodine in the reaction and avoid sublimation on the condenser apparatus.

Compound 2, known as 2-iodo-3,4-dimethoxybenzoic acid sodium salt is slowly added in a controlled manner to a slurry of compound 3, known as 2-hydroxy phenylacetic acid and potassium tert-butoxide in dimethylformamide in the presence of 1% copper (I) chloride. After the reaction is complete, the copper catalyst is removed by filtration after reduction with sodium dithionite. Crude 2-[2-(carboxylmethyl)phenoxy]-3,4-dimethylbenzoic acid, known as compound 4, is crystallized upon the addition of sulfuric acid and re-crystallization through the corresponding sodium salt from water/ethyl acetate/acetic acid.

2-[2-(Carboxylmethyl)phenoxy]-3,4-dimethylbenzoic acid, known as compound 4, goes through a cyclization process in sulfuric acid at high temperature before it is crystallized in tetrohydrofuran/water/acetic acid via the corresponding sodium salt to produce 5,6-dimethyl-9- oxo-9H-xanthen-4-yl acetic acid, known as compound 5 in Scheme 1.

An alternative is to cyclize 2-[2-(carboxylmethyl)phenoxy]-3,4-dimethylbenzoic acid, known as compound 4, in acetic acid in the presence of methane sulfonic acid, to produce 5,6- dimethyl-9-oxo-9H-xanthen-4-yl acetic acid, known as compound 5 in Scheme 1.

Both methods enable an easy isolation of 5,β-dimethyl-9-oxo-9H-xanthen-4-yt acetic acid, known as compound 5 in Scheme 1 , which crystallizes as coarse crystals in pure colorless form. The purification steps described above are not specific only to the synthesis 5,6~dimethyt-9-oxo-9H-xanthen-4-yl acetic acid. The purification steps may be useful for other sparingly soluble compounds which can be dissolved in water as their water soluble salt.

A further step would be the sodium salt formation of 5,6-diemthyl-9-oxo-9H-xanthen-4-yI acetic acid. For example, 5,6-diemthyl-9-oxo-9H-xanthen-4-yl acetic acid sodium salt can be prepared by the following reaction:

Scheme 2

(5,6-DimethyI-9-oxo-9H-xanthen-4- {5,6-DimethyI-9-oxo-9H-xanthen-4- yl)-acetic acid yt)-acetic acid sodium salt

a: NaOH, water/acetone

The process of preparing 5,6-diemthyl-9-oxo-9H-xanthen-4-yl acetic acid sodium salt yields a near colorless solution. The method for determining the color of the solution is illustrated in the European Pharmacopoeia.

The following examples are intended to illustrate the invention and are not to be construed as being limitations thereof. If not mentioned otherwise, the processes described herein above are conducted under inert atmosphere, preferably under nitrogen atmosphere. All evaporations are performed under reduced pressure, preferably between about 5 and

600 mbar. The structure of products and starting materials is confirmed by standard analytical methods, e.g., melting points (mp) and spectroscopic characteristics, e.g., MS, NMR. Abbreviations used are those conventional in the art. Example 1 Preparation of 2-iodo-3,4-dimethoxybenzoic acid sodium salt (compound 2)

To a suspension of 3,4-dimethyl anthranilie acid (1 ) (82.5 g) in water (300 ml_), add sodium hydroxide 30% (70 g). Most of the solid dissolves rapidly during the addition at 20-40⁰C, The dissolution is complete upon stirring for ca. 1 hour at 30-40⁰C to form a dark brownish solution which should be filtered over cellulose. The clear filtrate is then added to concentrated sulfuric acid (200 g) and water (300 mL) in such a way to keep the temperature below 50⁰C. During the addition 3,4-dϊmethylanthranylϊc acid sulfate crystallizes to form a thick but stirrable slurry which is cooled to -5° (jacket - 10°C). At this temperature, an aqueous solution of sodium nitrite (38 g) is added slowly in such a way to keep the temperature below -5° to 0⁰C. At this stage a brownish solution is formed with foam on the surface. This solution is added slowly over 2-3 hours to a hot mixture of: Water (200 mL), concentrated sulfuric acid (20 g), potassium iodide (300 g), iodine (50 g) and heptanes (100 mL) under reflux at 75-80⁰C. After the addition, maintain stirring for an additional 10-20 minutes until no gas evolves anymore. Then cool down to 40-50°C and add sodium hydrogen sulfite solution 40% (55 g) in such a way to keep the temperature between 40-50⁰C. Then add sodium hydroxide 30% (about 420 g) in such a way to keep the temperature between 40-50⁰C (in order to set the pH between 2-3). Then add ethyl acetate (500 mL); stir for 30 minutes, then separate the layers and remove the lower aqueous phase. If required, filter the Interface over cellulose. Wash the remaining organic phase with brine (20% NaCI solution, 100 mL), and separate again the lower aqueous layer. Then concentrate the organic phase under vacuum and add methanol (250 mL), and filter the solution over cellulose. Weight the filtrate and take a sample for titration. Then add sodium methoxide 30% (about 84 g depending from the assay performed previously). Then add ethyl acetate (1000 mL) and remove the methanol by distillation under vacuum (about 300 mbar at Jacket 60⁰C) and replace it continuously with ethyl acetate in such a way to maintain the volume constant (replace about 1000 mL distillate with fresh ethyl acetate). At this stage, the desired product crystallizes out. Stir about 30 minutes at 30-50⁰C. Then cool down to O⁰C, and stir about 2 hours. Then collect the solid by filtration and wash with ethyl acetate (400 mL). Dry the solid under vacuum at 60⁰C. Yield: 113.7 g of compound (2), Example 2 Preparation of 2-[2-(carboκylmethyl)phenoxy]-3,4-elimethyIbenzoic acid (Compound 4)

To a solution of 2-hydroxy-phenylacetic acid (3) (136.4 g, 880 mmol) in dry dimethylformamide (1200 mL) add potassium tert-butoxide (207.2 g 1792 mmole). The solution is heated to 80⁰C and seeded with the corresponding 2-hydroxy-phenyfacetic acid di-potassium salt. After 30 minutes of stirring, a suspension of 2-hydroxy-phenylacetic acid di-potassium salt is obtained. At this stage, a slurry of copper (1) chloride (0.8 g, 8 mmole) in dimethylformamide (38 mL) is added. Followed by the addition drop-wise of a solution of 2-lodo-3,4- dimethoxybenzoic acid sodium salt (238.4 g 800 ⁰C mmole) in dimethyl-formamide (800 mL). After the addition, the reaction mixture is stirred at 85⁰C for 2 hours. Most of the solvent dimethylformamide is removed by distillation under reduced pressure. Water (1520 mL) is added to the residue, as well as sodium dithionite (57.6 g, 228 mmole). The resulting aqueous solution is heated to 100⁰C and kept under reflux for 1.5 hours. Then, the fine suspension is cooled to 20-25⁰C and charcoal (8 g) is added. After 30 minutes stirring, the latter is filtered over a small path of cellulose. Then the clear filtrate is acidified to pH of 2-3 with concentrated sulphuric acid (about 96 g). The precipitated solid is collected, washed with water (1200 mL) and submitted as it to the following purification step: The dump solid (about 300 g) is suspended in water (600 mL) and brought into solution at a pH 7-8 by the addition of sodium hydroxide 30% solution (about 139 g). Then the resulting solution is dropped slowly to a hot solution of acetic acid (160 g) in ethyl acetate (1600 mL) in such a way to maintain a gentle reflux. Once half of the aqueous solution is added, seed crystals of pure 2-[2- (carboxylmethyl)phenoxy]-3,4-dimethylbenzoic acid (4) are added. After the addition, the resulting slurry is stirred under reflux for 1 hour. Then it is cooled to 0⁰C and kept at this temperature for 1 hour. Then the pure solid is isolated by filtration , washed with ethyl acetate (600 mL) and water 400 mL) and dried under reduced pressure at 60⁰C to yield pure compound (4) (192.3 g).

Example 3 Preparation of S.β-dimethyJ-S-oxo-iH-κanthen-S-yl-acetic acid (compound 5)

Compound (4) (15 g), methane sulfonic acid (15 g) and acetic acid (120 mL) are heated to reflux (118°C). To the resulting solution acetic anhydride (15 g) is added drop wise over 10-20 minutes. Immediately after the addition, crystallization occurs spontaneously. After stirring for an additional 30 minutes, the slurry is cooled to 15-20⁰C. The crystals are collected by filtration, washed with acetic acid (15 mL) followed by water (60 mL) and dried at 60⁰C under vacuum for approximately 12 hours. Yield: 13.3 g. Compound (5) obtained this way can be purified in the same way as described above after dilution with aqueous sodium hydroxide and addition of acetic acid in presence of tetrahydrofuran.

Example 4 Preparation of 5,6-dimethyl-9-oxo-9H-xanthen-4-yl-acetic acid (compound 5)

Pure compound (4) (150 g, 500 mmol) is added portion wise to a stirred solution of cone. H₂SO₄ (460 g, 96% strength) at 100⁰C. After the addition, stirring continues for 1 hour, then the temperature is lowered to 80°C and water (500 mL) is added in such a way to keep the temperature between 80-100⁰C. At this stage the resulting suspension can be filtered in order to isolate crude compound (7) or the compound is processed as following: To the resulting suspension, sodium hydroxide (1284 g, 9.6 mole) is added in such a way to keep the temperature between 40-60°C and to bring the pH >11. Then, tetrahydrofuran (600 mL) is added, and the resulting emulsion is allowed to let stand without stirring at 6O⁰C for phase separation. After removal of the lower aqueous phase, pure water (400 mL) is added, followed by acetic acid (60 g, 1 mole) added slowly at 65°C (under reflux). Once 10% acetic acid is added, seed (100 mg) suspended in water (3 mL) is added. After the addition, stirring under reflux is maintained for 1 hour. Afterwards the suspension is cooled within 2 hours to 15-25⁰C, aged for 1 hour and filtered to collect the coarse crystal of pure 5,6-dimethyl-9-oxo-9H-xanthen- 4-yl-acetic acid ((5): DMXAA, 124.3 g).

Example 5 Preparation 5,6-dimethyl-9-oxo-9H-xanthen-4-yl-acetic acid sodium salt (compound 6)

Prior to crystallization, 30% concentrated NaOH is prepared by adding 45 g of CSS to 105 g of water keeping the temperature below IT 50⁰C. The flask is flushed with nitrogen to prevent the formation of sodium carbonate.

In a double jacketed glass reactor 236.4 g of 5,β-dimethyl-9-oxo-9H-xanthen-4-yt-acetic acid is added to a mixture of 625.2 g water and 720 g ACT. The suspension is heated to IT 50 ⁰C and ca. 112 g of the prepared sodium hydroxide solution is added. The target pH should be between 9 and 10. The light yellow solution is then stirred for another 30 min. If more NaOH is required, the NaOH is added to meet the pH in the desired range. The solution is filtered (IT between 45 ⁰C and 5O⁰C) into a second reactor with a JT of 40 ⁰C. The filter and the filter line are washed with 154 ml of an ACT/water mixture 1:1 by weight. The clear solution is cooled to IT 35 ⁰C and seeded with 0.32 g of 5,6-dimethyl-9-oxo-9H-xanthen-4-yl-acetic acid, dispersed in a mixture of 0,4 g water and 4.8 g ACT. The thin suspension is further cooled to IT 25 °C within 4 h. At this temperature, 780 g ACT is dosed within 4 hours. After cooling to IT 0⁰C within 8 hours, the suspension is stirred for at least another hour at this temperature. The suspension is filtered and washed with a mixture of 360 g ACT/ 48g water in two portions. The wet fitter cake is dried at 700 mbar and 45 ⁰C until the solvent specifications have been reached (PAKs).

Example 6 Method for Analyzing the Color of the Final Product of 5,6-dimethyl-9-oxo- 9H-xanthen-4-yl-acetic acid sodium salt

In the European Pharmacopoeia the coloration of a solution is compared to scale of standard solutions of descending color intensity, e.g. the series Y1 - Y7 (yellow), BY1 - BY7 (brown- yellow) or B1 - B9 (brown). Solutions of 5,6-dimethyl-9-oxo-9H-xanthen-4-yl-acetic acid sodium salt from six batches are compared against the European Pharmacopoeia and all six batches are comparable to BY5 or BY6 on the scale.

-B-

Claims

What is claimed is;

1. A method for preparing 5,6-dimethyI-9-oxo-9H-xanthen-4-yl-acetic acid having the following formula (I):

or a pharmaceutically acceptable salt thereof, comprising reacting 2-iodo-3,4~dimethoxybenzoic acid sodium salt with 2-hydroxy phenylacetic acid and potassium tert-butoxide in dimethylformamide salt in the presence of 1% copper (I) chloride to produce 2-[2-(carboxylmethyl)phenoxy]-3,4-dimethylbenzoic add; and cyclizing the 2-[2-(carboxylmethyl)phenoxy]-3,4-dimethylbenzoic acid before crystallizing in a mixture comprising tetrahydrofuran, water and acetic acid.

2. The method according to Claim 1 , wherein the cyclizing of 2-[2- (carboxylmethyl)phenoxy]-3,4-dimethylbenzoic acid occurs in sulfuric acid at high temperature.

3. The method according to Claim 1 , wherein the cyclizing of 2-[2- (carboxylmethyl)phenoxy]-3,4-dimethylbenzoic acid occurs in acetic acid in the presence of methane sulfonic acid and acetic anhydride.

4. The method according to Claim 1 , wherein 2-iodo-3,4-dimethoxybenzoic acid sodium salt is slowly added in a controlled manner to a slurry of 2-hydroxy phenylacetic acid di-potassium salt in the presence of 1% copper (I) chloride.

5. The method according to Claim 1 , wherein the 1% copper (I) chloride is removed by filtration after reduction with sodium dithionite.

6. The method according to Claim 1 , wherein 2-[2-{carboxylmethyl)phenoxy]-3,4- dϊmethylbenzoic acid is crystallized upon the addition of sulfuric acid and re-crystallization through the corresponding sodium salt from water/ethyl acetate/acetic acid.

7. The method according to Claim 1 , wherein 5,6-dimethyI-9-oxo-9H-xanthen-4-yl-acetic acid is crystallized upon the addition of acetic acid through the corresponding sodium salt from THF water.

8. The method according to Claim 1 , wherein 5,6-dimethyi-9-oxo-9H-xarrthen-4-yl-acetic acid is reacted with sodium hydroxide to form 5,6-dimethyl-9-oxo-9H-xanthen-4-yl-acetic acid sodium salt.

9. The method according to Claim 1 , wherein 5,6-dimethyl-9-oxo-9H-xanthen-4-yl-acetic acid is colorless.

10. 5,6-dϊemthyl-9-oxo-9H-xanthen-4-yl acetic acid sodium salt.

11. 5,6-dimethyl-9-oxo-9H-xanthen-4-yl-acetic acid produced by the process comprising reacting 2-iodo-3,4-dimethoxybenzoic acid sodium salt with 2-hydroxy phenylacetic acid and potassium tert-butoxide in dimethylformamide salt in the presence of 1% copper (I) chloride to produce 2-[2-(carboxylmethyl)phenoxy]-3,4-dimethylbenzoic acid; and cyclizing the 2-[2- (carboxylmethyl)phenoxy]-3,4-dimethylbenzoic acid before crystallizing in a mixture comprising tetrahydrofuran, water and acetic acid.

12. The method according to Claim 11 , wherein the cyclizing of 2-[2- (carboxylmethyI)phenoxy]-3,4-dimethylbenzoic acid occurs in sulfuric acid at high temperature.

13. The method according to Claim 11 , wherein the cyclizing of 2-[2- (carboxylmethyl)phenoxy]-3,4-dimethylbenzoic acid occurs in acetic acid in the presence of methane sulfonic acid and acetic anhydride.

14. The method according to Claim 11, wherein 2-iodo-3,4-dimethoxybenzoic acid sodium salt is slowly added in a controlled manner to a slurry of 2-hydroxy phenylacetic acid di- potassium salt in the presence of 1% copper (I) chloride.

15. The method according to Claim 11, wherein the 1% copper (I) chloride is removed by filtration after reduction with sodium dithionite.

16. The method according to Claim 11, wherein 2-[2-(carboxyImethyI)phenoxy]-3,4- dimetbylbenzoic acid is crystallized upon the addition of sulfuric acid and re-crystallization through the corresponding sodium salt from water/ethyl acetate/acetic acid.

17. The method according to Claim 11 , wherein 5,6-dimethyl-9-oxo-9H-xanthen-4-yl-acetic acid is crystallized upon the addition of acetic acid through the corresponding sodium salt from THF water.

18. The method according to Claim 11, wherein 5,6-dimethyl-9-oxo-9H-xanthen-4-yI-acetic acid is reacted with sodium hydroxide to form 5,6-dimethyI-9-oxo-9H-xanthen-4-yI-acetic acid sodium salt.

19. The method according to Claim 11, wherein 5,6-dimethyl-9-oxo-9H-xanthen-4-y!-acetic acid is a colorless product.